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United States Patent |
5,145,684
|
Liversidge
,   et al.
|
September 8, 1992
|
Surface modified drug nanoparticles
Abstract
Dispersible particles consisting essentially of a crystalline drug
substance having a surface modifier adsorbed on the surface thereof in an
amount sufficient to maintain an effective average particle size of less
than about 400 nm, methods for the preparation of such particles and
dispersions containing the particles. Pharmaceutical compositions
containing the particles exhibit unexpected bioavailability and are useful
in methods of treating mammals.
Inventors:
|
Liversidge; Gary G. (West Chester, PA);
Cundy; Kenneth C. (Pottstown, PA);
Bishop; John F. (Rochester, NY);
Czekai; David A. (Honeoye Falls, NY)
|
Assignee:
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Sterling Drug Inc. (New York, NY)
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Appl. No.:
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647105 |
Filed:
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January 25, 1991 |
Current U.S. Class: |
424/489; 424/495; 424/499 |
Intern'l Class: |
A61K 009/14 |
Field of Search: |
424/495,489,499
|
References Cited
U.S. Patent Documents
2671750 | Mar., 1954 | Macek | 514/179.
|
4107288 | Aug., 1978 | Oppenheim | 424/499.
|
4540602 | Sep., 1985 | Motoyama | 424/495.
|
4826689 | May., 1989 | Violanto | 424/489.
|
4851421 | Jul., 1989 | Iwasaki et al. | 514/352.
|
Foreign Patent Documents |
411629 | Feb., 1991 | EP.
| |
2282330 | Nov., 1990 | JP.
| |
2185397 | Jul., 1987 | GB.
| |
2200048 | Jul., 1988 | GB.
| |
Other References
Lachman et al., "the Theory and Practice of Industrial Pharmacy", Chapter
2, Milling (1986).
Remington's Pharmaceutical Sciences 17th Edition, Chapter 20, Schott, H.,
"Colloidal Dispersions".
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Benston, Jr.; William E.
Attorney, Agent or Firm: Rosenstein; Arthur H., Davis; William J.
Claims
What is claimed is:
1. Particles consisting essentially of 99.9-10% by weight of a crystalline
drug substance having a solubility in water of less than 10 mg/ml, said
drug substance having a non-crosslinked surface modifier adsorbed on the
surface thereof in an amount of 0.1-90% by weight and sufficient to
maintain an effective average particle size of less than about 400 nm.
2. The particles of claim 1 having an effective average particle size of
less than 250 nm.
3. The particles of claim 1 having an effective average particle size of
less than 100 nm.
4. The particles of claim 1 wherein said drug substance is selected from
analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic
agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents,
antiepileptics, antihistamines, antihypertensive agents, antimuscarinic
agents, antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents, anxiolytic
sedatives, astringents, beta-adrenoceptor blocking agents, contrast media,
corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging
agents, diuretics, dopaminergics, haemostatics, immuriological agents,
lipid regulating agents, muscle relaxants, parasympathomimetics,
parathyroid calcitonin, prostaglandins, radio-pharmaceuticals, sex
hormones, anti-allergic agents, stimulants, sympathomimetics, thyroid
agents, vasodilators and xanthines.
5. The particles of claim 1 wherein said drug substance is a steroid.
6. Particles consisting essentially of 99.9-10% by weight of a crystalline
drug substance having a solubility in water of less than 10 mg/ml, said
drug substance having a non-crosslinked surface modifier absorbed on the
surface thereof in an amount of 0.1-90% by weight and sufficient to
maintain an effective average particle size of less than about 400 nm,
wherein said drug substance is selected from the group consisting of
Danazol,
5.alpha.,17.alpha.,-1'-(methylsulfonyl)-1'H-pregn-20-yno-[3,2-c]-pyrazol-1
7-ol, piposulfam, piposulfan, camptothecin, and
ethyl-3,5-diacetamido-2,4,6-triiodobenzoate.
7. The particles of claim 1 wherein said surface modifier is selected from
the group consisting of gelatin, casein, lecithin, gum acacia,
cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium
stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers,
polyoxyethylene caster oil derivatives, polyoxyethylene sorbitan fatty
acid esters, polyethylene glycols, polyoxyethylene stearates, colloidol
silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose
phthalate, noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone.
8. The particles of claim 1 wherein said surface modifier is selected from
the group consisting of polyvinylpyrrolidone, an ethylene oxide-propylene
oxide block copolymer, lecithin, an alkyl aryl polyether sulfonate, gum
acacia, sodium dodecylsulfate, and a dioctylester of sodium sulfosuccinic
acid.
9. Particles consisitng essentially of 80-40% by weight of crystalline
danazol having polyvinyl pyrrolidone adsorbed on the surface thereof in an
amount of 20-60% by weight and sufficient to maintain an effective average
particle size of less than about 100 nm.
10. Particles consisting essentially of 99.9-10% by weight of crystalline
5.alpha., 17.alpha.,-1'-(methylsulfonyl)-1'H-pregn-20-yno-pyrazol-17-ol
having an ethylene oxide propylene-oxide block copolymer adsorbed on the
surface thereof in an amount of 0.1-90% by weight and sufficient to
maintain an effective average particle size of less than about 400 nm.
11. A stable dispersion consisting essentially of a liquid dispersion
medium and the particles of claim 1.
12. The dispersion of claim 11 wherein said dispersion medium is water.
13. The dispersion of claim 11 wherein said dispersion medium is selected
from the group consisting of safflower oil, ethanol, t-butanol, hexane and
glycol.
14. A pharmaceutical composition comprising the particles of claim 1 and a
pharmaceutically acceptable carrier therefor.
15. A method of treating a mammal comprising the step of administering to
the mammal an effective amount of the pharmaceutical composition of claim
14.
16. A method of preparing the particles of claim 1 comprising the steps of
dispersing a drug substance in a liquid dispersion medium and wet grinding
said drug substance in the presence of rigid grinding media having an
average particle size of less than 3 mm and a surface modifier to reduce
the particle size of said drug substance to an effective average particle
size of less than about 400 nm.
17. A method of preparing the particles of claim 1 comprising the steps of
dispersing a drug substance in a liquid dispersion medium, wet grinding
said drug substance in the presence of rigid grinding media having an
average particle size of less than 3 mm, thereafter contacting said drug
substance with a surface modifier by mixing said surface modifier with
said dispersion medium to form particles having an effective average
particle size of less than about 400 nm.
18. The method of claim 17 further including the step of subjecting the
dispersion medium containing said drug substance and said surface modifier
to ultrasonic energy.
19. The method of claim 16 wherein said grinding media have an average
particle size of less than 1 mm.
20. The method of claim 16 wherein said grinding media have a density
greater than 3 g/cm.sup.3.
Description
FIELD OF THE INVENTION
This invention relates to drug particles, methods for the preparation
thereof and dispersions containing the particles. This invention further
relates to the use of such particles in pharmaceutical compositions and
methods of treating mammals.
BACKGROUND OF THE INVENTION
Bioavailability is the degree to which a drug becomes available to the
target tissue after administration. Many factors can affect
bioavailability including the dosage form and various properties, e.g.,
dissolution rate of the drug. Poor bioavailability is a significant
problem encountered in the development of pharmaceutical compositions,
particularly those containing an active ingredient that is poorly soluble
in water. Poorly water soluble drugs, i.e., those having a solubility less
than about 10 mg/ml, tend to be eliminated from the gastrointestinal tract
before being absorbed into the circulation. Moreover, poorly water soluble
drugs tend to be unsafe for intravenous administration techniques, which
are used primarily in conjunction with fully soluble drug substances.
It is known that the rate of dissolution of a particulate drug can increase
with increasing surface area, i.e., decreasing particle size.
Consequently, methods of making finely divided drugs have been studied and
efforts have been made to control the size and size range of drug
particles in pharmaceutical compositions. For example, dry milling
techniques have been used to reduce particle size and hence influence drug
absorption. However, in conventional dry milling, as discussed by Lachman,
et al., The Theory and Practice of Industrial Pharmacy, Chapter 2,
"Milling", p. 45, (1986), the limit of fineness is reached in the region
of 100 microns (100,000 nm) when material cakes on the milling chamber.
Lachman, et al. note that wet grinding is beneficial in further reducing
particle size, but that flocculation restricts the lower particle size
limit to approximately 10 microns (10,000 nm). However, there tends to be
a bias in the pharmaceutical art against wet milling due to concerns
associated with contamination. Commercial airjet milling techniques have
provided particles ranging in average particle size from as low as about 1
to 50 .mu.m (1,000-50,000 nm).
Other techniques for preparing pharmaceutical compositions include loading
drugs into liposomes or polymers, e.g., during emulsion polymerization.
However, such techniques have problems and limitations. For example, a
lipid soluble drug is often required in preparing suitable liposomes.
Further, unacceptably large amounts of the liposome or polymer are often
required to prepare unit drug doses. Further still, techniques for
preparing such pharmaceutical compositions tend to be complex. A principal
technical difficulty encountered with emulsion polymerization is the
removal of contaminants, such as unreacted monomer or initiator, which can
be toxic, at the end of the manufacturing process.
U.S. Pat. No. 4,540,602 (Motoyama et al.) discloses a solid drug pulverized
in an aqueous solution of a water-soluble high molecular substance using a
wet grinding machine. However, Motoyama et al. teach that as a result of
such wet grinding, the drug is formed into finely divided particles
ranging from 0.5 .mu.m (500 nm) or less to 5 .mu.m (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems
comprising a substance in the form of spherical particles smaller than 500
nm. However, the method involves a precipitation effected by mixing a
solution of the substance and a miscible non-solvent for the substance and
results in the formation of non-crystalline nanoparticle. Furthermore,
precipitation techniques for preparing particles tend to provide particles
contaminated with solvents. Such solvents are often toxic and can be very
difficult, if not impossible, to adequately remove to pharmaceutically
acceptable levels to be practical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to
1,000 nm containing a biologically or pharmacodynamically active material.
However, the particles comprise a crosslinked matrix of macromolecules
having the active material supported on or incorporated into the matrix.
It would be desirable to provide stable dispersible drug particles in the
submicron size range which can be readily prepared and which do not
appreciably flocculate or agglomerate due to interparticle attractive
forces and do not require the presence of a crosslinked matrix. Moreover,
it would be highly desirable to provide pharmaceutical compositions having
enhanced bioavailability.
SUMMARY OF THE INVENTION
We have discovered stable, dispersible drug nanoparticles and a method for
preparing such particles by wet milling in the presence of grinding media
in conjunction with a surface modifier. The particles can be formulated
into pharmaceutical compositions exhibiting remarkably high
bioavailability.
More specifically, in accordance with this invention, there are provided
particles consisting essentially of a crystalline drug substance having a
surface modifier adsorbed on the surface thereof in an amount sufficient
to maintain an effective average particle size of less than about 400 nm.
This invention also provides a stable dispersion consisting essentially of
a liquid dispersion medium and the above-described particles dispersed
therein.
In another embodiment of the invention, there is provided a method of
preparing the above-described particles comprising the steps of dispersing
a drug substance in a liquid dispersion medium and applying mechanical
means in the presence of grinding media to reduce the particle size of the
drug substance to an effective average particle size of less than about
400 nm. The particles can be reduced in size in the presence of a surface
modifier. Alternatively, the particles can be contacted with a surface
modifier after attrition.
In a particularly valuable and important embodiment of the invention, there
is provided a pharmaceutical composition comprising the above-described
particles and a pharmaceutically acceptable carrier therefor. Such
pharmaceutical composition is useful in a method of treating mammals.
It is an advantageous feature that a wide variety of surface modified drug
nanoparticles free of unacceptable contamination can be prepared in
accordance with this invention.
It is another advantageous feature of this invention that there is provided
a simple and convenient method for preparing drug nanoparticles by wet
milling in conjunction with a surface modifier.
Another particularly advantageous feature of this invention is that
pharmaceutical compositions are provided exhibiting unexpectedly high
bioavailability.
Still another advantageous feature of this invention is that pharmaceutical
compositions containing poorly water soluble drug substances are provided
which are suitable for intravenous administration techniques.
Other advantageous features will become readily apparent upon reference to
the following Description of Preferred Embodiments.
DESCRIPTION OF PREFERRED EMBODIMENTS
This invention is based partly on the discovery that drug particles having
an extremely small effective average particle size can be prepared by wet
milling in the presence of grinding media in conjunction with a surface
modifier, and that such particles are stable and do not appreciably
flocculate or agglomerate due to interparticle attractive forces and can
be formulated into pharmaceutical compositions exhibiting unexpectedly
high bioavailability. While the invention is described herein primarily in
connection with its preferred utility, i.e., with respect to
nanoparticulate drug substances for use in pharmaceutical compositions, it
is also believed to be useful in other applications such as the
formulation of particulate cosmetic compositions and the preparation of
particulate dispersions for use in image and magnetic recording elements.
The particles of this invention comprise a drug substance. The drug
substance exists as a discrete, crystalline phase. The crystalline phase
differs from a non-crystalline or amorphous phase which results from
precipitation techniques, such as described in EPO 275,796 cited above.
The invention can be practiced with a wide variety of drug substances. The
drug substance preferably is present in an essentially pure form. The drug
substance must be poorly soluble and dispersible in at least one liquid
medium. By "poorly soluble" it is meant that the drug substance has a
solubility in the liquid dispersion medium of less than about 10 mg/ml,
and preferably of less than about 1 mg/ml. A preferred liquid dispersion
medium is water. However, the invention can be practiced with other liquid
media in which a drug substance is poorly soluble and dispersible
including, for example, aqueous salt solutions, safflower oil and solvents
such as ethanol, t-butanol, hexane and glycol. The pH of the aqueous
dispersion media can be adjusted by techniques known in the art.
Suitable drug substances can be selected from a variety of known classes of
drugs including, for example, analgesics, anti-inflammatory agents,
anthelmintics, anti-arrhythmic agents, antibiotics (including
penicillins), anticoagulants, antidepressants, antidiabetic agents,
antiepileptics, antihistamines, antihypertensive agents, antimuscarinic
agents, antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents, anxiolytic
sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor
blocking agents, blood products and substitutes, cardiac inotropic agents,
contrast media, corticosteroids, cough suppressants (expectorants and
mucolytics), diagnostic agents, diagnostic imaging agents, diuretics,
dopaminergics (antiparkinsonian agents), haemostatics, immuriological
agents, lipid regulating agents, muscle relaxants, parasympathomimetics,
parathyroid calcitonin and biphosphonates, prostaglandins,
radio-pharmaceuticals, sex hormones (including steroids), anti-allergic
agents, stimulants and anoretics, sympathomimetics, thyroid agents,
vasodilators and xanthines. Preferred drug substances include those
intended for oral administration and intravenous administration. A
description of these classes of drugs and a listing of species within each
class can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth
Edition, The Pharmaceutical Press, London, 1989, the disclosure of which
is hereby incorporated by reference in its entirety. The drug substances
are commercially available and/or can be prepared by techniques known in
the art.
Representative illustrative species of drug substances useful in the
practice of this invention include:
17-.alpha.-pregno-2,4-dien-20-yno-[2,3-d]-isoxazol-17-ol (Danazol);
5.alpha.,17.alpha.,-1'-(methylsulfonyl)-1'H-pregn-20-yno[3,2-c]-pyrazol-17-
ol (Steroid A);
piposulfam;
piposulfan;
camptothecin; and
ethyl-3,5-diacetoamido-2,4,6-triiodobenzoate
In particularly preferred embodiments of the invention, the drug substance
is a steriod such as danazol or Steroid A or an antiviral agent.
The particles of this invention contain a discrete phase of a drug
substance as described above having a surface modifier adsorbed on the
surface thereof. Useful surface modifiers are believed to include those
which physically adhere to the surface of the drug substance but do not
chemically bond to the drug.
Suitable surface modifiers can preferably be selected from known organic
and inorganic pharmaceutical excipients. Such excipients include various
polymers, low molecular weight oligomers, natural products and
surfactants. Preferred surface modifiers include nonionic and anionic
surfactants. Representative examples of excipients include gelatin,
casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth,
stearic acid, benzalkonium chloride, calcium stearate, glyceryl
monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan
esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as
cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene
sorbitan fatty acid esters, e.g., the commercially available Tweens,
polyethylene glycols, polyoxyethylene stearates, colloidol silicon
dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose
phthalate, noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most
of these excipients are described in detail in the Handbook of
Pharmaceutical Excipients, published jointly by the American
Pharmaceutical Association and The Pharmaceutical Society of Great
Britain, the Pharmaceutical Press, 1986, the disclosure of which is hereby
incorporated by reference in its entirety. The surface modifiers are
commercially available and/or can be prepared by techniques known in the
art.
Particularly preferred surface modifiers include polyvinyl pyrrolidone,
Pluronic F68 and F108, which are block copolymers of ethylene oxide and
propylene oxide, Tetronic 908, which is a tetrafunctional block copolymer
derived from sequential addition of ethylene oxide and propylene oxide to
ethylenediamine, dextran, lecithin, Aerosol OT, which is a dioctyl ester
of sodium sulfosuccinic acid, available from American Cyanamid, Duponol P,
which is a sodium lauryl sulfate, available from DuPont, Triton X-200,
which is an alkyl aryl polyether sulfonate, available from Rohm and Haas,
Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available
from ICI Specialty Chemicals, and Carbowax 3350 and 934, which are
polyethylene glycols available from Union Carbide. Surface modifiers which
have found to be particularly useful include polyvinylpyrrolidone,
Pluronic F-68, and lecithin.
The surface modifier is adsorbed on the surface of the drug substance in an
amount sufficient to maintain an effective average particle size of less
than about 400 nm. The surface modifier does not chemically react with the
drug substance or itself. Furthermore, the individually adsorbed molecules
of the surface modifier are essentially free of intermolecular
crosslinkages.
As used herein, particle size refers to a number average particle size as
measured by conventional particle size measuring techniques well known to
those skilled in the art, such as sedimentation field flow fractionation,
photon correlation spectroscopy, or disk centrifugation. By "an effective
average particle size of less than about 400 nm" it is meant that at least
90% of the particles have a weight average particle size of less than
about 400 nm when measured by the above-noted techniques. In preferred
embodiments of the invention, the effective average particle size is less
than about 250 nm. In some embodiments of the invention, an effective
average particle size of less than about 100 nm has been achieved. With
reference to the effective average particle size, it is preferred that at
least 95% and, more preferably, at least 99% of the particles have a
particle size less than the effective average, e.g., 400 nm. In
particularly preferred embodiments, essentially all of the particles have
a size less than 400 nm. In some embodiments, essentially all of the
particles have a size less than 250 nm.
The particles of this invention can be prepared in a method comprising the
steps of dispersing a drug substance in a liquid dispersion medium and
applying mechanical means in the presence of grinding media to reduce the
particle size of the drug substance to an effective average particle size
of less than about 400 nm. The particles can be reduced in size in the
presence of a surface modifier. Alternatively, the particles can be
contacted with a surface modifier after attrition.
A general procedure for preparing the particles of this invention is set
forth below. The drug substance selected is obtained commercially and/or
prepared by techniques known in the art in a conventional coarse form. It
is preferred, but not essential, that the particle size of the coarse drug
substance selected be less than about 100 .mu.m as determined by sieve
analysis. If the coarse particle size of the drug substance is greater
than about 100 .mu.m, then it is preferred that the particles of the drug
substance be reduced in size to less than 100 .mu.m using a conventional
milling method such as airjet or fragmentation milling.
The coarse drug substance selected can then be added to a liquid medium in
which it is essentially insoluble to form a premix. The concentration of
the drug substance in the liquid medium can vary from about 0.1-60%, and
preferably is from 5-30% (w/w). It is preferred, but not essential, that
the surface modifier be present in the premix. The concentration of the
surface modifier can vary from about 0.1 to about 90%, and preferably is
1-75%, more preferably 20-60%, by weight based on the total combined
weight of the drug substance and surface modifier. The apparent viscosity
of the premix suspension is preferably less than about 1000 centipoise
The premix can be used directly by subjecting it to mechanical means to
reduce the average particle size in the dispersion to less than 400 nm. It
is preferred that the premix be used directly when a ball mill is used for
attrition. Alternatively, the drug substance and, optionally, the surface
modifier, can be dispersed in the liquid medium using suitable agitation,
e.g., a roller mill or a Cowles type mixer, until a homogeneous dispersion
is observed in which there are no large agglomerates visible to the naked
eye. It is preferred that the premix be subjected to such a premilling
dispersion step when a recirculating media mill is used for attrition.
The mechanical means applied to reduce the particle size of the drug
substance conveniently can take the form of a dispersion mill. Suitable
dispersion mills include a ball mill, an attritor mill, a vibratory mill,
and media mills such as a sand mill and a bead mill. A media mill is
preferred due to the relatively shorter milling time required to provide
the intended result, i.e., the desired reduction in particle size. For
media milling, the apparent viscosity of the premix preferably is from
about 100 to about 1000 centipoise. For ball milling, the apparent
viscosity of the premix preferably is from about 1 up to about 100
centipoise. Such ranges tend to afford an optimal balance between
efficient particle fragmentation and media erosion.
The grinding media for the particle size reduction step can be selected
from rigid media preferably spherical or particulate in form having an
average size less than about 3 mm and, more preferably, less than about 1
mm. Such media desirably can provide the particles of the invention with
shorter processing times and impart less wear to the milling equipment.
The selection of material for the grinding media is not believed to be
critical. We have found that zirconium oxide, such as 95% ZrO stabilized
with magnesia, zirconium silicate, and glass grinding media provide
particles having levels of contamination which are believed to be
acceptable for the preparation of pharmaceutical compositions. However,
other media, such as stainless steel, titania, alumina, and 95% ZrO
stabilized with yttrium, are expected to be useful. Preferred media have a
density greater than about 3 g/cm.sup.3.
The attrition time can vary widely and depends primarily upon the
particular mechanical means and processing conditions selected. For ball
mills, processing times of up to five days or longer may be required. On
the other hand, processing times of less than 1 day (residence times of
one minute up to several hours) have provided the desired results using a
high shear media mill.
The particles must be reduced in size at a temperature which does not
significantly degrade the drug substance. Processing temperatures of less
than about 30.degree.-40.degree. C. are ordinarily preferred. If desired,
the processing equipment can be cooled with conventional cooling
equipment. The method is conveniently carried out under conditions of
ambient temperature and at processing pressures which are safe and
effective for the milling process. For example, ambient processing
pressures are typical of ball mills, attritor mills and vibratory mills.
Processing pressures up to about 20 psi (1.4 kg/cm.sup.2) are typical of
media milling.
The surface modifier, if it was not present in the premix, must be added to
the dispersion after attrition in an amount as described for the premix
above. Thereafter, the dispersion can be mixed, e.g., by shaking
vigorously. Optionally, the dispersion can be subjected to a sonication
step, e.g., using an ultrasonic power supply. For example, the dispersion
can be subjected to ultrasonic energy having a frequency of 20-80 kHz for
a time of about 1 to 120 seconds.
The relative amount of drug substance and surface modifier can vary widely
and the optimal amount of the surface modifier can depend, for example,
upon the particular drug substance and surface modifier selected, the
critical micelle concentration of the surface modifier if it forms
micelles, etc. The surface modifier preferably is present in an amount of
about 0.1-10 mg per square meter surface area of the drug substance. The
surface modifier can be present in an amount of 0.1-90%, preferably 20-60%
by weight based on the total weight of the dry particle.
As indicated by the following examples, not every combination of surface
modifier and drug substance provides the desired results. Consequently,
the applicants have developed a simple screening process whereby
compatible surface modifiers and drug substances can be selected which
provide stable dispersions of the desired particles. First, coarse
particles of a selected drug substance of interest are dispersed in a
liquid in which the drug is essentially insoluble, e.g., water at 5% (w/w)
and milled for 60 minutes in a DYNO-MILL under the standard milling
conditions which are set forth in Example 1 which follows. The milled
material is then divided into aliquots and surface modifiers are added at
concentrations of 2, 10 and 50% by weight based on the total combined
weight of the drug substance and surface modifier. The dispersions are
then sonicated (1 minute, 20 kHz) to disperse agglomerates and subjected
to particle size analysis by examination under an optical microscope
(1000.times.magnification). If a stable dispersion is observed, then the
process for preparing the particular drug substance surface modifier
combination can be optimized in accordance with the teachings above. By
stable it is meant that the dispersion exhibits no flocculation or
particle agglomeration visible to the naked eye at least 15 minutes, and
preferably, at least two days or longer after preparation.
The resulting dispersion of this invention is stable and consists of the
liquid dispersion medium and the above-described particles. The dispersion
of surface modified drug nanoparticles can be spray coated onto sugar
spheres or onto a pharmaceutical excipient in a fluid-bed spray coater by
techniques well known in the art.
Pharmaceutical compositions according to this invention include the
particles described above and a pharmaceutically acceptable carrier
therefor. Suitable pharmaceutically acceptable carriers are well known to
those skilled in the art. These include non-toxic physiologically
acceptable carriers, adjuvants or vehicles for parenteral injection, for
oral administration in solid or liquid form, for rectal administration,
and the like. A method of treating a mammal in accordance with this
invention comprises the step of administering to the mammal in need of
treatment an effective amount of the above-described pharmaceutical
composition. The selected dosage level of the drug substance for treatment
is effective to obtain a desired therapeutic response for a particular
composition and method of administration. The selected dosage level
therefore, depends upon the particular drug substance, the desired
therapeutic effect, on the route of administration, on the desired
duration of treatment and other factors. As noted, it is a particularly
advantageous feature that the pharmaceutical compositions of this
invention exhibit unexpectedly high bioavailability as illustrated in the
examples which follow. Furthermore, it is contemplated that the drug
particles of this invention provide more rapid onset of drug action and
decreased gastrointestinal irritancy.
It is contemplated that the pharmaceutical compositions of this invention
will be particularly useful in oral and parenteral, including intravenous,
administration applications. It is expected that poorly water soluble drug
substances, which prior to this invention, could not have been
administered intravenously, may be administered safely in accordance with
this invention. Additionally, drug substances which could not have been
administered orally due to poor bioavailability may be effectively
administered in accordance with this invention.
While applicants do not wish to be bound by theoretical mechanisms, it is
believed that the surface modifier hinders the flocculation and/or
agglomeration of the particles by functioning as a mechanical or steric
barrier between the particles, minimizing the close, interparticle
approach necessary for agglomeration and flocculation. Alternatively, if
the surface modifier has ionic groups, stabilization by electrostatic
repulsion may result. It was surprising that stable drug particles of such
a small effective average particle size and free of unacceptable
contamination could be prepared by the method of this invention.
The following examples further illustrate the invention.
EXAMPLE 1
PVP Modified Danazol Particles Prepared in a Ball Mill
A nanoparticulate dispersion of Danazol was prepared using a DYNO-MILL
(Model KDL, manufactured by Willy A. Bachoffen AG Maschinenfabrik). The
following ingredients were added to a glass vessel and agitated on a
roller for 24 hours to dissolve the polyvinylpyrrolidone surface modifier.
Polyvinylpyrrolidone K-15 (made by GAF)--98 g
High purity water--664 g
Subsequently, 327 grams of dry powdered Danazol was added to the above
solution and rolled for one week. This step aided in evenly dispersing the
Danazol in the surface modifier solution, thereby reducing the treatment
time required in the media mill. The Danazol was purchased in a micronized
form (average particle size of about 10 microns) from Sterling Drug Inc.
The particles had been prepared by a conventional airjet milling
technique. This premix was added to a holding vessel and agitated with a
conventional propeller mixer at low speed to maintain a homogeneous
mixture for the media milling event. The media mill was prepared
accordingly for the media milling process. The mill grinding chamber was
partially filled with silica glass spheres and the premix was continuously
recirculated through the media mill operating at the following conditions:
Grinding vessel: water jacketed stainless steel chamber
Premix flow rate: 250 ml per minute
Available volume of grinding vessel: 555 ml
Media volume: 472 ml of glass beads
Media type: size range of 0.5-0.75 mm silica glass beads, unleaded
(distributed by Glen Mills, Inc.)
Recirculation time: 240 min
Residence time: 60 min
Impeller speed: 3000 RPM, tangential speed 1952 ft/min (595 m/min)
Grinding vessel coolant: water
Coolant temperature: 50.degree. F. (10.degree. C.)
After recirculating the slurry for 240 minutes, a sample of the dispersion
was removed and evaluated for particle size distribution using a
sedimentation field flow fractionator (made by DuPont). The particles were
determined to have a number average diameter of 77.5 nm and a weight
average diameter of 139.6 nm. The particle size of the dispersion ranged
in size from 3-320 nm.
EXAMPLE 2
PVP Modified Danazol Particles Prepared in a Ball Mill at Low Solids.
A nanoparticulate dispersion of Danazol was prepared using a ball mill
process. A 600 ml cylindrical glass vessel (inside diameter=3.0 inches
(7.6 cm)) was filled approximately halfway with the following grinding
media:
Grinding media: zirconium oxide grinding spheres (made by Zircoa, Inc.)
Media size: 0.85-1.18 mm diameter
Media volume: 300 ml
The following dry ingredients were added directly to this glass vessel:
Danazol (micronized): 10.8 g
Polyvinylpyrrolidone K-15: 3.24 g
High purity water: 201.96 g
Danazol was purchased in the micronized form (average particle size 10
microns) from Sterling Drug Inc. and the polyvinylpyrrolidone was K-15
grade produced by GAF. The cylindrical vessel was rotated horizontally
about its axis at 57% of the "critical speed". The critical speed is
defined as the rotational speed of the grinding vessel when centrifuging
of the grinding media occurs. At this speed the centrifugal force acting
on the grinding spheres presses and holds them firmly against the inner
wall of the vessel. Conditions that lead to unwanted centrifuging can be
computed from simple physical principles.
After 5 days of ball milling, the slurry was separated from the grinding
media through a screen and evaluated for particle size with the
sedimentation field flow fractionator. The number average particle
diameter measured was 84.9 nm and the weight average particle diameter was
169.1 nm. The particles varied in size from 26 to 340 nm. The amount and
type of surface modifier was sufficient to provide colloidal stability to
agglomeration and to maintain a homogeneous blend of ingredients assuring
precise material delivery during subsequent processing steps.
BIOAVAILABILITY TESTING
Bioavailability of Danazol from the nanoparticulate dispersion described
above was compared to that from a suspension of unmilled Danazol in fasted
male beagle dogs. The unmilled material was prepared as a suspension in
the same manner as the dispersion, with the exception of the ball milling
process. Both formulations were administered to each of five dogs by oral
gavage and plasma obtained via a cannula in the cephalic vein. Plasma
Danazol levels were monitored over 24 hours. The relative bioavailability
of Danazol from the nanoparticulate dispersion was 15.9 fold higher than
from the Danazol suspension containing Danazol particles having an average
particle size of about 10 microns prepared by conventional airjet milling.
Comparison of oral plasma levels with dose corrected plasma levels
following intravenous administration of Danazol gave a mean absolute
bioavailability (.+-.SEM) of 82.3.+-.10.1% for the nanoparticulate
dispersion and 5.1.+-.1.9% for the unmilled material.
EXAMPLE 3
PVP Modified Danazol Particles Prepared in a Ball Mill at High Solids
A nanoparticle dispersion of Danazol was prepared using 1 mm diameter glass
grinding media (0.85-1.18 mm from Potters Industries). A cylindrical glass
vessel having a diameter of 2.75 inches (7.0 cm) with a volume of 400 ml
was charged with 212 ml of unleaded glass grinding media. The following
ingredients were added to this vessel:
30.4 g of micronized Danazol
9.12 g of Polyvinylpyrrolidone K-15
112.48 g of high purity water
This vessel was rotated horizontally on its axis at a controlled rotational
speed of 80.4 revolutions per minute (50% of critical speed) for 5 days.
The slurry was immediately separated from the grinding media and evaluated
for particle size and grinding media attrition using inductively coupled
plasma emissions (ICP). The particle size measured with a sedimentation
field flow fractionator yielded a number average diameter of 112.7 nm and
a weight average diameter of 179.3 nm. The extent of media attrition was
measured to establish the purity of the final dispersion using an
inductively coupled plasma-atomic emission spectroscopy method. The level
of silicon in the final dispersion was less than 10 parts of elemental
silicon per million parts of the slurry.
EXAMPLE 4
PVP Modified Danazol Particles
A nanoparticle dispersion of Danazol was prepared for clinical evaluation
using a ball milling dispersion method. This dispersion was prepared by
milling with glass grinding media. The grinding media used was:
Media type: 0.85-1.18 mm unleaded glass spheres
Media quantity: 6100 ml
The media was added to a 3 gallon porcelain jar. The following ingredients
were then added to the jar:
1000 g Danazol (micronized)
300 g Polyvinylpyrrolidone K-15
3700 g high purity water
The vessel was rolled 5 days at a rotational speed of 39.5 revolutions per
minute (50% critical speed). The liquid slurry was separated from the
grinding media with a screen and used to prepare solid oral doses for
clinical studies. The dispersion was assessed for particle size using the
sedimentation field flow fractionator and was measured to have a number
average diameter of 134.9 nm and a weight average diameter of 222.2 nm.
The level of contamination from the grinding media was measured (by ICP)
to be 36 parts of silicon per million parts of dispersion. Less than 5 ppm
of aluminum was detected. X-ray powder diffraction data of the starting
powder was compared with the dispersed Danazol and showed the crystal
structure morphology of the solid dispersed particles was unchanged by the
dispersion process.
EXAMPLE 5
PVP Modified Danazol Particles
A nanoparticulate dispersion of Danazol was prepared using a laboratory
media mill and glass grinding media. The media mill was equipped with a 50
ml grinding chamber and the mill was a "Mini" Motormill manufactured by
Eiger Machinery Inc.
The media mill was operated at the following process conditions:
Bead charge: 42.5 ml glass spheres
Rotor speed: 5000 RPM (2617 feet per minute (798 m/min) tangential speed)
Grinding media: 0.75-1.0 mm unleaded glass beads (distributed by Glens
Mills)
The dispersion formula was prepared by dissolving 27 g of
polyvinylpyrrolidone in 183 g of water and agitated in a steel vessel with
a 50 mm "Cowles" type blade until the solution was clear and free of
undissolved PVP polymer. The rotational speed of the mixer was maintained
at 5000 RPM. 90 g of micronized Danazol was slowly added to this blend
with the same mixing for 30 min. 200 cc of the premix was added to the
holding tank of the mill and recirculated for 5 hours and 51 minutes. The
final residence time in the grinding zone was 40 minutes.
The final average particle size was measured and determined to have a
number average diameter of 79.9 nm and a weight average diameter of 161.2
nm. The particles varied in size from 30-415 nm. The level of attrition
from erosion of the grinding media and grinding vessel were measured (by
ICP) to be 170 ppm of iron and 71 ppm silicon. The crystal structure was
determined by X-ray diffraction to be unchanged by the dispersion process.
EXAMPLE 6
Lecithin Modified Steroid A Particles
A nanoparticulate dispersion of Steroid A was prepared by ball milling with
zirconium oxide grinding beads. The dispersion was prepared in the absence
of a surface modifier and a post addition of Lecithin and a sonication
step were required to stablize the dispersed phase of Steroid A and
prevent agglomeration and rapid sedimentation. A fine particle dispersion
of Steroid A was prepared by ball milling the following ingredients:
5 g Steroid A
95 g high purity water
Steroid A was in the form of unmilled coarse grains having a particle size
of about 100 .mu.m and ranging in size up to about 400 .mu.m.
The following process conditions were used:
Media: 135 ml
Vessel volume: 240 ml
Media type: 0.85-1.18 mm Zirbeads (manufactured by Zircoa Inc.)
Milling time: 4 days
Milling speed: 86 RPM (50% critical speed)
After four days of ball milling the slurry was separated from the grinding
media through a screen. One gram of this unstabilized slurry was added to
10 g of an aqueous solution of Lecithin (1% Centrolex "P" by weight in
high purity water, Lecithin manufactured by Central Soya Company, Inc.)
and mixed by vigorous shaking, followed by a sonication step for 20
seconds using an ultrasonic horn (Model 350 Branson Ultrasonic Power
Supply, Horn Diameter=0.5 inch (1.27 cm), Power setting=2). The slurry was
sized under a microscope. An Olympus BH-2 optical microscope equipped with
phase contrast illumination was used to observe the size and condition of
the dispersion.
A drop of the above dilute slurry was placed between a microscope slide and
glass cover slip and observed microscopically at high magnification (1,000
times) and compared to the slurry similarly diluted with water only (no
surface modifier). The unmodified dispersion exhibited extensive particle
agglomeration. The particle size of the unmodified dispersion was more
than 10 microns and the unmodified dispersion exhibited no Brownian
Motion. Brownian motion is the oscillatory or jiggling motion exhibited by
particles in a liquid that fall in the size range of less than about 1
micron. The Lecithin modified particles exhibited rapid Brownian motion.
The thus observed dispersion had the characteristics and appearance
consistent with a number average particle size of less than 400 nm.
Furthermore, it is expected that additional milling would lead to further
particle size reduction.
EXAMPLE 7
Alkyl Aryl Polyether Sulfonate Modified Steroid A
Example 6 was repeated except that the Lecithin was replaced with Triton
X-200 (manufactured by Rohm and Haas). Similar results were observed.
EXAMPLE 8
Gum Acacia Modified Steroid A
Example 6 was repeated except that the Lecithin was replaced with gum
acacia (available from Eastman Kodak Co.) Similar results were observed.
EXAMPLE 9
Sodium Lauryl Sulfate Modified Steroid A
Example 6 was repeated except that the Lecithin was replaced with sodium
lauryl sulfate (available as Duponol ME from DuPont, Inc.). Similar
results were observed.
EXAMPLE 10
Steroid A Modified with a Dioctylester of Sodium Sulfosuccinic Acid
Example 6 was repeated except that the Lecithin was replaced with Aerosol
OT (available from American Cyanamid Chemical Products, Inc.). Similar
results were observed.
EXAMPLE 11
Steroid A Modified with a Block Copolymer of Ethylene Oxide and Propylene
Oxide
Example 6 was repeated except that the Lecithin was replaced with Pluronic
F68 (available from BASF Corp.). Similar results were observed.
EXAMPLE 12
Steroid A Modified with a Block Copolymer of Ethylene Oxide and Propylene
Oxide
A nanoparticulate dispersion of Steroid A was prepared by ball milling with
zirconium oxide grinding media for 5 days. 70 cc of grinding media were
added to a 115 cc vessel followed by:
2.5 g Steroid A
0.75 g of Pluronic F68
46.75 g high purity water
The resulting mixture was ball milled for 5 days at 50% of the critical
rotational speed. The final dispersion was separated from the grinding
media and microscopically evaluated for particle size as in Example 6. The
dispersion exhibited rapid Brownian Motion and no particles were larger
than 1 micron. Most particles were less than 400 nm.
EXAMPLE 13
Lecithin Modified Steroid A Particles
Example 12 was repeated except that the Pluronic F68 was replaced with
Centrolex P. No particles larger than 1 micron were observed
microscopically and most were less than 400 nm.
EXAMPLE 14
Steroid A Particles Modified with a Block Copolymer of Ethylene Oxide and
Propylene Oxide
A nanoparticulate dispersion of Steroid A was prepared by a ball milling
process. The following ingredients were added to a cylindrical 0.95 l
vessel. The vessel was filled approximately halfway with the following
grinding media:
Grinding media: 0.85-1.18 mm diameter zirconium oxide spheres (made by
Zircoa)
The following dispersion ingredients were added directly to the glass
vessel:
18 g Steroid A
4.5 g Pluronic F68 (purchased from BASF Corp.)
336.6 g high purity water
Steroid A was purchased from Sterling Drug Inc. in the form of unmilled
tabular crystals having an average particle size of approximately 100
.mu.m.
The vessel was rotated concentrically on its axis at 50% critical speed for
5 days. After this time 4.45 g of Pluronic F68 was added to the slurry and
rolled for 5 more days at the same conditions. The slurry was then
discharged and separated from the grinding media and evaluated for
particle size using the sedimentation field flow fractionator. The number
average particle size measured was 204.6 nm and the weight average
particle size was 310.6 nm. The particle size distribution ranged from
approximately 68-520 nm. The dispersion was examined with an optical
microscope. It exhibited excellent particle integrity, free flocculation
and agglomeration. The dispersion particles exhibited rapid Brownian
motion.
BIOAVAILABILITY TESTING
Bioavailability of Steroid A from the nanoparticulate dispersion described
above was compared to that from a suspension of unmilled Steroid A (having
an average particle size of about 100 .mu.m) in male beagle dogs. The
unmilled material was prepared as a suspension in the same manner as the
dispersion, with the exception of the ball milling process. Both
formulations were administered to each of five dogs by oral gavage and
plasma obtained via a cannula in the cephalic vein. Plasma Steroid A
levels were monitored over 24 hours. The relative bioavailability of
Steroid A from the nanoparticulate dispersion was 7.1 fold higher than
from the unmilled Steroid A suspension. Comparison of oral plasma levels
with dose corrected plasma levels following intravenous administration of
Steroid A gave a mean absolute bioavailability (.+-.SEM) of 14.8.+-.3.5%
for the nanoparticulate dipersion and 2.1.+-.1.0% for the unmilled
material.
COMPARATIVE EXAMPLE A
A dispersion of Steroid A was prepared using a ball milling process with
zirconium oxide grinding beads. The dispersion was prepared in the absence
of a surface modifier and a post-sonication step was used to minimize
flocculation and reaggregation.
A fine particle dispersion was prepared by ball milling the following
ingredients:
5 g Steroid A
95 g high purity water
The following process conditions were used:
Grinding media: 135 ml
Vessel volume: 240 ml
Grinding media: 0.85-1.18 mm Zirbeads XR
Milling time: 4 days
Milling speed: 86 RPM (50% critical speed)
After four days of ball milling, the slurry was separated from the grinding
media through a screen. One gram of the unstablized slurry was blended
with 10 grams of high purity water and mixed by vigorous shaking, followed
by a sonication step for 20 seconds using an ultrasonic horn (Model 350
Branson Ultrasonic Power Supply, Horn diameter=0.5 inch, Power setting=2).
The slurry was sized under a microscope. An optical microscope equipped
with phase contrast illumination was used to observe the condition of the
dispersion.
A drop of the dilute slurry was placed between a microscope slide and a
glass cover slip and observed at high magnification (400.times.). The
dispersion exhibited severe particle aggregation. The aggregate size was
greater than 10 microns and exhibited no Brownian particle movement.
COMPARATIVE EXAMPLE B
Comparative Example A was repeated except that 1 gram of the slurry was
added to 10 grams of a dilute solution (1% by weight) of PVP K-15. The
resultant dispersion after 6 days was aggregated. The aggregate size was
at least 5 microns. After 6 days of holding, the dispersion settled
completely leaving a clear supernatant and a layer of Steroid A sediment.
COMPARATIVE EXAMPLE C
Comparative Example B was repeated except that the 1% PVP solution was
replaced with a 1% solution of purified sodium methyl oleoyl taurate
(available from GAF as Igepon T and subsequently purified at Eastman
Kodak). After 6 days the dilute dispersion was partially flocculated and
had many aggregates larger than 1 micron.
COMPARATIVE EXAMPLE D
Comparative Example B was repeated except that 1 gram of slurry was added
to 10 grams of a 1% aqueous solution of polyethylene glycol (available
from Union Carbide as PEG 3350). The dispersion after sonification was
flocculated with particles larger than 35 microns.
COMPARATIVE EXAMPLE E
Comparative Example B was repeated except that the dispersion was diluted
with an aqueous 1% solution of gum tragacanth (available from Eastman
Kodak). This freshly prepared dispersion exhibited flocculation with
particles 10 microns and larger.
COMPARATIVE EXAMPLE F
A dispersion of Danazol was prepared by ball milling with zirconium oxide
grinding spheres. A cylindrical glass vessel was filled about halfway with
the following ingredients:
Grinding media: 135 ml 0.85-1.18 mm Zirbeads XR
5 g Danazol
1 g PVP K-15
94 g high purity water
This vessel was rotated horizontally on its axis at a controlled speed of
50% critical speed (85 RPM) for 4 days. The slurry was discharged and
separated from the grinding media through a screen and examined for
particle size with an optical microscope. The slurry was examined for
particle size after holding it for 4 days at room temperature (23.degree.
C.). A drop of undiluted slurry was placed between a glass microscope
slide and a glass cover slip and observed optically at high magnification
(400X). The slurry was partially aggregated with particles up to 10
microns in diameter. Unlike Examples 1-5, the amount of PVP present was
insufficient to hinder particle agglomeration.
The invention has been described in detail with particular reference to
preferred embodiments thereof, but it will be understood that variations
and modifications can be effected within the spirit and scope of the
invention.
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